Numerous research publications have demonstrated the benefits of continuous glucose monitoring for better glucose control and reduced glycated hemoglobin (HbA1c) levels;however, to improve efficacy, significant improvements in the performance of implanted glucose sensors are required. The proposed Phase 1 research is focused on developing a rapid, microsecond, minimally invasive, continuous glucose monitor that addresses many of the limitations of currently marketed Continuous Glucose Monitors (CGMs) including: the body's immune response also known as biofouling, dynamic range, sensor lag, and accuracy in the hypoglycemic range (<70 mg/dL). Included in the Specific Aims is the development of a new technology for measuring enzymatic reactions occurring on a microsecond scale that have not been described previously. In addition, this research will yield a better understanding of both chemical and electrochemical processes occurring within 20E of a biosensor surface. The results of this research will also yield a near instantaneous indication of the effects of the body's immune response on the sensor output, thus enabling error free in vivo glucose measurements with essentially zero sensor lag. This will reduce the overall lag-time associated with interstitial fluid glucose measurements;thereby, significantly improving accuracy. Inaccuracy has limited FDA pre-market approval of CGMs to adjunctive therapy to fingerstick monitoring. This means all readings from the CGM must be confirmed by fingerstick measurements prior to adjustments in insulin dosage or diet. In the long-term, for continuous glucose monitoring to gain wider consumer acceptance and reimbursement by Medicare and health Insurers, accuracy needs to be improved and the requirement for periodic re-calibration of CGM sensors reduced or eliminated. Successful completion of this proposed Phase 1 research will provide significant advances in continuous glucose monitoring technology that have the potential to resolve many of the accuracy and calibration issues faced by users. Furthermore, improved accuracy and the ability to correct for biofouling will provide additional efficacy data that health insurance providers are demanding for reimbursement, and bring the concept of the artificial pancreas one step closer to reality. PUBLIC HEALTH RELEVANCE: The lack of sustained control and inadequate monitoring of glucose concentration to avoid glycemic excursions comes at a high cost to the national healthcare system, and has a demonstrated impact on disease progression and secondary complications for patients with diabetes and impaired glucose tolerance. Current 1st generation FDA approved continuous glucose monitoring (CGM) devices have gained limited or conditional acceptance by insulin dependent diabetics, regulatory agencies, and third- party insurance payers due to accuracy problems and the need for frequent recalibration. The micro- second sampling rate and signal processing algorithms of the proposed CGM system overcome existing technical limitations and provide a resolution of measurement and control on a scale orders of magnitude higher than current devices, thereby making the "closed loop" artificial pancreas a near-term reality.